The body’s defense against infection

1. The body’s defense against infection Chapter 8 & complement Ch7

2. Pathogens have different mechanisms to induce tissue damage

6. Innate Immunity

7. The Innate Immune Response

8. Innate Immunity:Complement provides an initial molecular defense against many microorganisms

9. Late 1800s: Combining bacteria with blood serum results in cell death. > 30 complement proteins / glycoproteins Membrane bound & free. Designation: C’ C1 – C9 Other letters: factor D, factor B. Historical Perspective

10. Complement proteins: Made in the liver as zymogens- activation by cleavage. Example: C4 Exception: C2: C2a = large fragment C2b = small fragment C4a C4b Overview: a = smaller fragment Diffusion & signaling b= larger fragment. remains bound to microbe

11. Function of complement: • Kuby- Immunology, fig. 13-1 (4th ed)

12. 1. Classical Pathway 2. Alternative Pathway 3. Lectin or MBL Pathway Pathways for activation require multiple steps categorized as: 1. Recognition 2. Enzyme activation 3. Biological activity Unique proteins for 1st 2 steps common proteins Three pathways for Complement activation:

13. (fig. 7.27, parham): Classical- antibody Lectin (MBP)- Mannose binding protein. Alternative- pathogens surface. Recognition of microorganisms & enzyme activation for each pathway:

14. All 3 pathways converge with the protein C3. • Enzyme activation to form a C3 convertase: (fig. 13.1 benjamini)

15. C4b-C2a

16. Unique Recognition & binding  * Formation of C3 convertase  Classical vs Alternative Classical vs Alternative Formation of C5 convertase  Formation of the membrane attack complex. Identical proteins *amplification steps!

17. The Classical Pathway Mediated by Ab recognition of microbe!

18. The classical pathway is initiated by: • Ab binding to the pathogen! • C1 proteins binds to the Fc of Ab. 1 C1q 2 C1r 2C1s

19. C1q- 18 polypeptides • 6 arms with globular heads- • Binds Fc on Ig (CH2 domains) 2 C1r + 2 C1s can be activated serine proteases.

20. planar form Molecular interaction of Ab with pathogen & C1 with Ab results in changes in conformation of IgM.

21. At least 3 binding sites exposed for C1q. Molecular interaction of Ab with pathogen & C1 with Ab results in changes in conformation.

22. C1 must bind @ least 2 Fc domains to be stable: • Staple form of IgM at least 3 binding sites. • 1 IgM can activate complement. • For IgG, 2 molecules must be as close as 30-40 nm for C1 binding. • > 1000 IgG necessary.

23. Upon binding Ab, C1 undergoes conformational changes leading to the activation of C1r & C1s: p. 210

24. Cleavage of C4 reveals a thioester bond- • Allows for binding of C4b to the target! p. 209

27. Upon binding Ab, C1 undergoes conformational changes leading to the activation of C1r & C1s: p. 210

28. Classical C3 Convertase Cleavage of C3 reveals a thioester!

29. Classical C3 convertase will cleave 1000s of C3 that bind to the pathogens surface.

30. C4b-2a-3b functions as the classical C5 convertase:

34. The Alternative Pathway for Complement Activation

35. Important for initial defense against microbes during innate immune responses- • Antibody Independent! • Alternative pathway starts with C3-H2O binding to bacteria, viruses or other pathogens. • Low levels of C3-H2O is present in plasma due to slow spontaneous hydrolysis of C3.

36. C3-H2O can bind B leading to the formation of the “fluid phase C3 convertase”, Bb-C3-H2O.

37. Following cleavage of C3, the C3bBb is formed & functions as the alternativeC3 convertase.

39. Properdin- Factor P. • Stablilizes C3b-Bb so it may cleave more C3. • May cleave over a million C3 molecules! • Protects Bb-C3b from inactivation by complement control mechanisms.

40. C3b-C3b-Bb functions as the C5 convertase in the alternative pathway.

43. Lectin Mediated Pathway for Complement Activation

44. Mannose-binding protein (MBP)- serum protein. • binds mannose on pathogen. • MBP-Associated serum protein (MASP)- • protease • Cleaves C4 & C2

46. Regulation of Complement Activation Regulatory Proteins Control Complement Activation:

47. Prevent the formation of classical C3 convertase. • C1 inhibitor (C1-INH): • Helps prevents C1 activation in serum. p. 218

49. p. 219 Inhibits the classical & alternative pathways! Factor H can bind to C3b better when the cell caries sialic Acid (human cells).

50. Human Cells carry surface proteins that inactivate complement: